Oral beta-RA Prevents and Rescues Obesity, Insulin Resistance and Hepatic Steatosis

Background and PurposeObesity is a major health problem, and it is linked to other diseases like type II diabetes, metabolic syndrome, and hepatic steatosis. Some treatments for obesity show low efficiency or side effects. Recently, the modulation Coenzyme Q (CoQ) metabolism has emerged as a potential target for the treatment of metabolic syndrome. This can be potentially achieved by using analogs of the precursor of CoQ biosynthesis, e.g., beta-resorcylic acid (beta-RA).Experimental approachWe evaluated the therapeutic effect of oral beta-RA in diet-induced obese (DIO) mice by molecular, biochemical, metabolic, morphological and phenotypic approaches in the serum, liver, white adipose tissue (WAT) and skeletal muscle.Key ResultsOral supplementation with beta-RA, taken in the chow, in DIO mice induces weight loss, improves glucose homeostasis by reducing insulin/glucagon ratio and gastric inhibitory peptide (GIP) levels in plasma, reduces WAT hypertrophy, and prevents hepatic steatosis. Moreover, the WAT, livers, and serum of untreated DIO mice show abnormalities in metabolites involved in glycolysis, the TCA cycle, and the urea cycle. These metabolic abnormalities were normalized in DIO mice that received beta-RA, a finding that is at least in part explained by a stimulation of the hepatic lipid metabolism and the normalization of mitochondrial CoQ metabolism in the WAT of the mice. Furthermore, the pharmacokinetic properties of beta-RA support the requirements of a sustained administration to maintain therapeutically relevant concentrations in plasma.Conclusion and Implicationbeta-RA is an efficient, safe, and translatable therapeutic option to treat and/or prevent obesity, metabolic syndrome and NAFLD.